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Methylation Can Turn Off Massive Gene Regions in Stem Cells

NEW YORK (GenomeWeb News) – Histone modifications added during cellular differentiation can alter the chromatin structure and turn off gene expression in large chunks of mouse and human genomes, according to a new study appearing yesterday in the advanced online edition of Nature Genetics.

A team of researchers from Johns Hopkins and Kyoto Universities used ChIP-chip analyses to compare the histone H3 lysine 9 dimethylation patterns in undifferentiated and differentiated mouse embryonic stem cells as well as mouse liver and brain cells. Their results suggest that "large organized chromatin K9 modifications," or LOCKs, are added to the genome during cellular differentiation, silencing large stretches of DNA.

These LOCKs, which influence the gene expression patterns in different cell types, appear to be conserved in human cells. And early results suggest that the loss of the epigenetic signals may increase cancer risk.

"These results suggest that LOCKs appear gradually during development, refining cells' functions as they differentiate into particular cell types," lead author Bo Wen, a post-doctoral fellow in researcher Andrew Feinberg's lab at Johns Hopkins University, said in a statement. "Our experiments suggest the whole forest of genes is changing, but people have been looking at the individual trees."

After initial ChIP-chip analyses of human placental cells indicated that histone H3 lysine 9 dimethylation (H3K9Me2) clustered across large regions of the genome, the researchers decided to look more closely at H3K9Me2 in various types of mouse cells.

Using mouse ENCODE arrays and custom mouse arrays, the researchers compared H3K9Me2 patterns in mouse liver and brain cells with those in differentiated and undifferentiated mouse embryonic stem cells.

Their results suggest that nearly 88 percent of the histone H3 lysine 9 chromosomal locations that were dimethylated in human cells were also modified in mouse liver cells, indicating that the modified regions were conserved between the species.

When the team compared the LOCK patterns in other mouse cell types, they found that these large-scale methylation events were more common in differentiated cells than in undifferentiated cells. For instance, roughly four percent of the undifferentiated embryonic stem cell genome carried LOCKs, compared with 31 percent of the differentiated embryonic stem cell genome, 45.6 percent of the liver cell genome, and 9.8 percent of the brain cell genome.

The average size of these modifications also increased along with differentiation, jumping from 43,000 bases in undifferentiated embryonic stem cells to 93,000 bases in differentiated stem cells and 235,000 bases in liver cells. The largest LOCKs were detected in liver cells, where they spanned as many as 4.9 million bases.

Gene expression waned in the LOCKed regions, the researchers found, with both LOCK and gene expression patterns varying by cell type.

"Genes that lay within LOCKs in the liver but not in the brain were largely silenced in liver but showed a broad range of expression in brain," the authors noted. "Similarly, genes in LOCKs in brain but not liver were largely silenced in brain but showed a broad range of expression in liver."

Along with providing new insights into stem cell biology and cellular differentiation, the findings may have implications for understanding a number of human conditions — including cancer. For example, in a preliminary set of experiments, the researchers found that there were considerably less of the genome in LOCKs in two human cancer cells lines than in human placental tissue or lymphoblastoid cell lines.

"In cancer, some of these LOCKS may become unlocked," senior author Feinberg said in a statement. "Sections of DNA that were silenced in a cell type might become active, giving cancer cells characteristics of other cell types that they're not supposed to have."

Overall, the researchers speculated that the histone methylation patterns they observed during differentiation may influence not only gene expression but also related processes such as nuclear organization and the formation of tightly-packed, silent chromosomal regions called heterochromatin.

In particular, they suggested that the addition of LOCKs may facilitate more intimate interactions between the genome and the nuclear membrane, particularly since LOCK locations in human cells often overlap with parts of the genome that interact with the nuclear lamina, a network of proteins on the inside of the nuclear envelope.

"In this model, in undifferentiated ES cells, only a small fraction of the genome is within LOCKs, and its nuclear positioning may be relatively distant from the nuclear membrane and show global expression," the authors suggested. "After differentiation, a much larger fraction of the genome is within LOCKs, in a tissue-specific manner. Chromosomes may be repositioned through the association of LOCKs and nuclear lamina, forming lineage-specific nuclear architectures."

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